EAS 2015 Disso Presentation_JHH_final

Practical Approach for Developing Dissolution Methods to Support Clinically Relevant SpecificationsJian‐Hwa Han, Patrick Marroum, and Gregory Webster, (AbbVie Inc.)

Xujin Lu, Nikoletta Fotaki, and Limin Zhang, (AAPS, IVRDT Focus Group)

2015 Eastern Analytical Symposium & Exposition18 November, 2015

Developing Clinically Relevant Dissolution Specifications| Eastern Analytical Symposium & Exposition| Date 18 Nov, 2015 | Copyright © 2015 AbbVie 2

• Dissolution Testing – a Review – General Expectations– Role of Dissolution– General Considerations – In Vitro

• Applications of Dissolution Testing • Expectations

– Biorelevant Dissolution Testing– Clinical‐Relevant Dissolution Specification

• Collaborative Efforts during Development• Phase Dependent Strategy for Method Development• Dissolution Testing ‐ Limitation • Concept of Curve Matching• Robust Product • Think Outside the Box & Summary

Outlines


A Dissolution Test is Expected to be:• Appropriately Discriminatory

– Formulation – Materials & Compositions (CMA*)– Manufacturing Parameters (CPP*)

– Lubrication– Blending Time– Compression Force, …, etc.

– Stability – Temperature, Humidity, Photosensitivity, and other Stresses

• Rugged/Robust• Reproducible (Reliable)

CMA: Critical Material Attribute CPP: Critical Process Parameters

Review –General Expectations


Review –Role of Dissolution in the Life Cycle of a Product

(Source: Dr. Patrick Marroum with slight modification.)

Full in vitro drug

release

All the learning for Dissolution method performance should be explored during Phase II under QbDconcept.


• Any in vitro dissolution method can be utilized• The method once defined should be the same for all formulations

tested (within a project/product)• The preferred dissolution apparatus is USP apparatus I or II used at

compendially recognized speeds• An aqueous medium either water or buffered solutions not

exceeding pH 6.8 is recommended• The coefficient of variation (% CV) for mean dissolution of a single

batch should be less than 10 % (Tighter %CV is expected for a good spec setting.)

• At least 80 % dissolution should be achieved with the proposed test

Review –General Considerations ‐ In Vitro Dissolution Testing

(Source: Dr. Patrick Marroum with slight modification.)


• Quality control test to assure batch to batch consistency(Be able to discriminate formulation/process differences.)

• Surrogate for bioavailability

– When different in vivo drug release characteristics are observed, the dissolution method is expected to be sensitive to pick up the differences even in the absence of a predictive IVIVC test

• Use for Justification of Biowaiver – Demonstration of Bioequivalency (for BCS 1 and BCS 3 products)

Applications of Dissolution Testing


Expectations –Biorelevant Dissolution Methods?

BiorelevantDissolution Testing* Predictive?

In Vitro In Vivo

It is desirable to have a method (any method) which is able to predict the in vivo drug performance!

Biorelevant Media:• FaSSIF• FeSSIF• Carbonate media

Equipment:• TIM/TNO• Artificial Stomach‐

Duodenum Model

Methods:• Artificial Stomach−

Duodenum Model• Biphasic Dissolution• pH Dilution Method

Knowledge obtained with in vitro tools aids understanding of DP in vivo performance

However, for dissolution testing, there is NO biorelevant method until we can prove the clinical relevancy.


Expectations –Clinical‐Relevant Dissolution Specification

(Biorelevant) Dissolution Method

Clinical Relevant Dissolution Spec

Reflect Performance

In Vitro In Vivo

(Matching the profiles!‐ Deconvolution &

Convolution)

Analytical Deliverable: Dissolution method to support Clinical‐relevant Dissolution Specifications!


Collaborations

Formulation:Product Design –

(Formulation & Process)

DMPK‐BA / Clinical PK:In Vivo Drug Performance

Analytical: In Vitro Drug

Release Evaluation


Phase Dependent Strategy – FIH (Pilot)

Activities Goal Needs

• Physical/Chemical properties of API

• Compatibility of Excipient

• Identify BCS Classificationof the drug if possible

Formulation: Suitable Formulation

Disso: Full Drug ReleasePK: Basic Info (e.g. Tmax,

Cmax, and AUC)

Formulation Design /Operation principle

For BCS 1 and 3 drugs, follow the FDA new guidance using the standard apparatus and conditions.

For BCS 2 and 4 drugs,Standard Apparatus and Conditions with minimal modifications

Responsibilities:• Formulation – Pilot Samples• Analytical – Assay• PK – Clinical Results


Phase Dependent Strategy –Phase 1b – 2b (Development)


1. Explore in vitro drug release behaviors under different disso method conditions.

2. Formulation screening bydisso method and compare disso data to clinical results.

3. Select the most relevant disso method according to formulation/process understanding and clinical results.•Material/process Variability CMA’s & CPP’s

•Minimize method variability

Formulation: • Formulation variability• Process sensitivityDissolution: • Reliable/Reproducible

Method• Clinical relevance may

not be established at this time but should be evaluated as early as possible

PK:• Animal studies may be

used during early development

• Deconvolution Absorption Profiles

• Establish Target Dissolution Profile

• Building the knowledge around Formulation and Process

• Design Space – Explore extreme conditions

• Clinical study to evaluate key formulation/process attributes on the drug release characteristics? ($$$ Cost & When to do it?)

• QbD: Decision whether in‐vitro drug release (disso) be used as end point to define design space and control strategy

• BCS Classification defined (or earlier!)


Phase Dependent Strategy –Phase 1b – 2b (Development) – continuedResponsibilities:• Formulation – To prepare samples with different key attributes (i.e.

formulation/process variables) to evaluate the impact on dissolution profile

• Analytical – Fully understand method variables, i.e. pH impact, RPM, addition of surfactants, and Apparatus differences. Select the appropriate method which can discriminate the formulation/process variables. Minimize the method variability.

• PK – Deconvolution absorption profiles. Define BCS classification. (Animal studies may be used during early development.)


Phase Dependent Strategy –Phase 2b ‐ 3 (Final Stage)


1. Process Validation.

2. Stage II (Final Stage) Method Validation.

3. IVIVC, as feasible

Formulation: • Process control –

Design Space Control Strategy

Dissolution: • Method is sensitive to

CMA’s and CPP’s• Method is capable to

reject non‐bioequivalent batches

PK:• Identify BE or non‐BE

batches

• Sound product knowledge with fully understoodformulation/process

• Identify CMA’s/CPP’s and set up control strategy to assure product quality

• Dissolution method is discriminating, robust and reproducible which can be used for QC purpose

• Clinical data with non‐BE samples to support dissolution specification


Dissolution Testing ‐ Limitation

• Using biorelevant media and specially designed equipment for dissolution testing do NOT guarantee clinically relevant results!

• Drug substance and formulation properties should be considered in the in vitro method development, and the process is a case‐by‐case activity.


Concept of Curve Matching: (I) Selecting Method Conditions

Dissolution Method Knowledge


Concept of Curve Matching: (II) Identify Discriminating Power

Need samples to achieve different in vivo profiles!

BE? or non‐BE ?


Robust Product: (I) No In Vitro Drug Release Difference

Prepare samples with up to +/‐20% variations of the key

attributes

Test samples by Dissolution (in vitro drug release) and select samples for Bio‐study

Are the samples Bio‐equivalent?

BE non‐BE

Develop New Dissolution Method

Setting Meaningful

Specifications & Control Strategy


Robust Product: (II) Define Product Control Space (Control Strategy)

Design Space

Knowledge Space

ProcessFormulation

BEBE

BE BE

Operation Space


Think Outside the Box!• How much has HPLC been improved over the last 30

years? • How much has Dissolution Testing changed over the

last 30 years?

Could we bring more freedom in operating Dissolution Apparatus?

USP App 1 and App 2 are the most QC friendly apparatus! How about:• pH Changes √• Temperature ≠ 37⁰ C (?)

• RPM Ramping (?)

• Other Controls (?)


• A Dissolution Test to support clinically relevant acceptance criterion/criteria can not be developed by Analytical/Disso group alone. It has to be a strong collaboration among Analytical, Formulation, and PK groups.

• Formulation has to specially prepare some “unordinary samples” to see the impact from CMA’s/CPP’s to the drug release for both in vivo and in vitro.

• PK group to design biostudies and collect clinical data. Establish the target profile for studied product. Collect in vivo data for those “unordinary samples” for information.

• Analytical to select the most appropriate dissolution testing conditions to match the “target dissolution file”. Compare the dissolution profiles of those “unordinary samples”, and set up the relevant specification.

• The teams working together to consolidate all the findings and define the “control space” for manufacturing process (control strategy) to assure the quality of the product.

Summary


Thanks to the following providers for the pictures used in this presentation:

• David Tan, AbbVie Singapore – Slide 14

• www.drug‐dissolution‐testing.com ‐ Slide 14

• Electrolab India P. Ltd. – Slide 19

• Wikimedia Commons, the free media repository – Slides 14 & 19

Acknowledge

Documents

EAS 2015 Disso Presentation_JHH_final